The induction of obesity has been known to be involved in an action of accelerating eating via proteins that are expressed in the hypothalamus such as neuropeptide Y5 receptor, or melanocortin receptor, an action of accelerating the synthesis of fatty acids via acyl-CoA carboxylase (ACC) or the like. Currently, as an anti-obesity drug, a neuropeptide Y5 receptor antagonist, a melanocortin receptor antagonist and an ACC inhibitor or the like have been developed. However, to date, an effective anti-obesity drug has not been found.
Fatty liver is a disease, which a neutral fat accumulates in the liver, and obesity are deemed as a major cause of developing it. However, similarly to an anti-obesity drug, an effective drug for treating fatty liver has not been found to date. In addition, regarding diabetes which is deemed as a representative example of a metabolic syndrome and which is deemed as a fundamental cause of lifestyle related diseases such as obesity or circulatory system diseases, sulfonylurea drugs, biguanides, alphaglucosidase and azolidine derivatives and the like have been developed. However, problems for side effect and efficacy thereof exist. Therefore, a more effective drug for treatment is expected to be developed.
A sphingomyelin synthetase (SMS) is an enzyme which synthesizes sphingomyelin(SM), a sphingolipid most abundant in a cell membrane, and plays an important role in cell death and survival (see, NPLs 1 and 2). SMS was identified in 2004, and are known to be present as two kinds, SMS1 and SMS2. SMS1 is known to be expressed in the Golgi body and be involved in de novo synthesis of SM. On the other hand, SMS2 is expressed in the Golgi body and cell membrane and unknown for its physiological function in detail (see, NPL 3) and merely suggested in NPLs 4-6 for the possibility of involving in arteriosclerosis.
To date, methods for ameliorating a metabolic syndrome by using neutral fat metabolism/absorbance inhibitors or inhibiting agents, agents for accelerating neutral fat metabolism or the like have been attempted. Specifically, these are drugs for ameliorating hyperlipidemia and type II diabetes by synthetic ligands of intranuclear receptor PPARs, drugs for ameliorating hyperlipidemia via inhibiting cholesterol synthesis by statin agents, or the like.
To date, an action of inducing obesity via controlling the synthesis of sphingolipids have not been known. A SMS inhibitor developed as anti-diabetes drug, anti-obesity drug or a drug for treating fatty liver does not exist, either.
On the other hand, RNAi is a phenomenon found by Fire et al in 1998 (NPL 7), in which a double stranded RNA strongly suppresses the expression of a target gene homologous thereto. It is recently taken notice since it is easier than conventional transgenic methods using a vector or the like, has a high specificity to the target and can be applied to a gene therapy. Among molecules that mediate RNAi, a short chain interfering RNA (siRNA) is advanced for its application (NPL 8). However, it has not been developed as an SMS inhibitor. It has not been known to have an effect of ameliorating a metabolic syndrome as an SMS inhibitor, either.